Alzheimer's disease (AD) is the most common dementing disorder in the United States. AD already is a major public health burden that is poised to burgeon in the next generation. There is a clear therapeutic imperative for AD and a critical need to quickly and robustly validate candidate protectants from observational studies to insure that the best possible agents advance to randomized clinical trials, and to discover new and safe neuroprotectants. The long-term objective of this project is to provide pathological and biochemical validation of candidate protectants and to aid in the discovery of new candidates for AD. The Adult Changes in Thought (ACT) study is an ongoing large population-based longitudinal study involving approximately 3,200 elderly individuals who were cognitively intact when enrolled. A unique and powerful feature of ACT is its extensive pharmacy database that extends back to 1986. We propose to use this pharmacy database to test the hypothesis that some commonly used therapeutics suppress pathological features of AD-type neurodegeneration in elderly individuals without dementia, individuals with prodromal dementia, and patients with incident AD. We will test this hypothesis by determining associations between documented exposure to therapeutics and pathologic endpoints obtained in this project. Therapeutics to be evaluated include antihypertensives, antioxidants, non-steroidal anti-inflammatory drugs, hormone replacement therapy in women, and emerging candidate protectants identified during the course of this project. Pathologic endpoints to be determined in multiple brain regions obtained by rapid autopsy protocol are: (1) magnitude of oxidative damage to neuronal membranes (2) dendritic and synaptic degeneration (3) protein insolubility (4) density and staging of histopathologic structures, viz., neuritic plaques, neurofibrillary tangles, and Lewy bodies. This study offers a unique opportunity to discover and validate candidate protectants from among commonly used therapeutics, an endeavor unlikely to be pursued by pharmaceutical industry, and will provide needed rational either for or against the advancement of candidate protectants in randomized clinical trials for prevention of AD.